This invention relates to a method of treating diseases caused by sebaceous gland disorders, especially acne, in humans and animals by inhibiting the secretions of such glands by use of acyl coA cholesterol acyl transferase (hereafter `ACAT`) inhibitors or prodrugs therefor (wherein the ACAT inhibitors and prodrugs are referred to hereafter as "active compounds").
Acne is a group of dermatological disorders which are associated with a variety of etiologies. The group of acnes includes chloroacne, ciliaris, cystic, keratosa and vulgaris. In its vulgaris form, it occurs primarily in the face and trunk areas, affecting the appearance of the patient. It probably causes more mental pain and anguish to those afflicted than many other diseases which, from a physical standpoint, may be much more severe. The basic lesion common to the family of diseases referred to as acnes is the comedo or "blackhead" of a pilosebaceous follicle. The condition may be mild and transient with only a few blackheads which can readily be ejected by pressure and are of little concern, or may be severe, persistent, and very disfiguring with the more serious cases causing cystic lesions and frequently leaving permanent scarring.
What appears to occur in the development of acnes is an initial filling up of the follicle with a viscous, keratinous material. This impaction of horny material is the whitehead and blackhead. As a result of bacterial growth in these horny impactions, the follicle ruptures initiating the inflammatory phase of the disease which takes the form of pustules, papules, cysts and nodules.
One of the commonly used methods for acne treatment is the use of "peeling", i.e., as astringent, agents for mild cases which cause exfoliation with the removal of some of the keratinous plugs. In the more serious cases where pustular or cystic lesions exists, the same are evacuated by incision and the contents expressed. Various other therapies have been employed, such as vaccine therapy, to assist in the control of chronic infection and increase the patient's resistance to Staphylococci; cortisone-type steroids; hormone therapy which is applicable only for female patients who may be put on routine contraceptive regimen with estrogens; antibacterial therapy for the treatment of extensive pustular or cystic acne where the patient may be treated with tetracyclines, penicillin, erythromycin, or other of the antibacterial agents, and, in come instances, general surgical skin planing may be used.
Although many different approaches have been used for the treatment of this almost universal affliction, none of the common topical treatments has been found to be particularly effective. Systematic administration of hormones and antibacterials has been shown to have some therapeutic merit but may be unacceptable for chronic therapy.
The administration of large oral doses of vitamin A has been suggested as being beneficial in acne, Straumford, J. V.: "Vitamin A: Its Effects on Acne", Northwest Med., 42, 219-225 (August 1943), although other investigators have felt it to be ineffective (Anderson, J. A. D. et al., "Vitamin A in Acne Vulgaris" Brit. Med. J., 2, 294-296 (August 1963); Lynch, F. W. et al., "Acne Vulgaris Treated with Vitamin A" Arch Derm., 55, 355, 357 (March 1947) and Mitchell, G. H. et al., "Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A" Arch. Derm., 64, 428-430 (October 1951).
Vitamin A acid has been applied topically (Beer, Von P., "Untersuchungen ber die Wirkung Vitamin A-Saure" Dermatologica, 124, 192-195 (March 1962) and Stuttgen, G., "Zur Lokalbehandlung von Keratosen mit Vitamin A-Saure" Dermatologica, 124, 65-80 (February 1962)) achieving good results in those hyperkeratotic disorders which are responsive to high oral doses of vitamin A. Among those treated by Beer and Stuttgen were patients with acne; however, these investigators reported no effective results on this disorder.
The treatment of acnes with isotretinoin and etretinate is described by J. A. Goldstein, et al. "Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion." J. Am Acad Dermatol, 6, 760-765 (1982). S. S. Shapiro et al. discuss treatment of acnes with various potential therapeutic entities in "Evaluation of Potential Therapeutic Entities for the Treatment of Acne" Pharmacology of Retinoids in the Skin. Pharmacol. Skin, Reichert and Shroot, eds, Karger, Basel, vol. 3, pp 104-122 (1989)).
Lambert, R. W., and Smith, R. E. have discussed the "[e]ffects of 13-cis-retinoic acid on the hamster Meibomian gland", J. Invest Derm, 93(2), 321-325 (1989) whereas the effects of retinoids on psoriasis is discussed by Lowe, N. J., and David M. in "Systemic Retinoids in Psoriasis: Comparative Efficacy and Toxicity", Pharmacology of Retinoids in the Skin. Pharmacol. Skin, vol. 3, pp 104-122, Reichert and Shroot eds, Karger, Basel, (1989).
U.S. Pat. No. 3,729,568 refers to the use of vitamin A acid (retinoic acid or tretinoin) in the treatment of acne vulgaris.
Co-pending International Patent Application PCT/US92/06485 teaches the use of vitamin A acid derivatives in the treatment of skin diseases including acne.
U.S. Pat. No. 4,703,110 describes the use of para substituted benzoic acid derivatives in the treatment of dermatological disorders including cystic acne.
U.S. Pat. No. 4,927,928 teaches the use of benzamido compounds in the treatment of dermatological diseases having an inflammatory and/or immunoallergic component, including acne vulgaris, senile acne and medicinal or professional acne.